The present invention relates to a therapeutic drug for an endotoxin blood symptom and multi-organ failure induced by it.
Endotoxins are lipopolysaccharides constituting cell membranes of Gram-negative bacteria, and their various physiological activities such as pyrexia, reduction in blood pressure, reduction in blood platelets, intravascular coagulation, promotion in capillary permeability, activation of complements, etc. are known. Therefore, if sepsis is induced through infection with Gram-negative bacteria, or if Gram-negative bacteria abnormally propagate in the large intestine, the concentration of the endotoxin in the blood increases so that the endotoxin blood symptom may appear. As various diseases caused by the endotoxin blood symptom, it is known that serious shock death may be induced or multi-organ failure may be provoked. As the multi-organ failure, hepatocirrhosis, fulminant hepatitis, acute renal failure, pulmonary failure, gastrointestinal bleeding, DIC (diffuse intravascular coagulation), etc. may be recited.
In order to prevent the endotoxin blood symptom, antibiotics have been formerly administrated for the purpose of suppressing the propagation of the Gram-negative bacteria as a source of generating the endotoxins. However, if a large amount of an antibiotic is administered, drug-resistant bacteria represented by MRSA come out to make the therapy more difficult, and the endotoxin blood symptom is aggravated by the release of the endotoxin from the Gram-negative bacteria killed by the antibiotic. Therefore, development of a therapeutic drug other than the antibiotics has been demanded.
From this purpose, antibodies against an endotoxin or a lipid A as a constituent component of the endotoxin has been developed. However, this measure have a drawback that since a neutralized effect differs depending upon the kinds of the Gram-negative bacteria, the therapeutic effect differs, too. Further, this measure has another drawback that since an antibody is produced against the endotoxin antibody by administrating a different kind of a protein, i.e., the antibody, side effects such as allergy, shock, etc. may occur in a continuous treatment.
The present invention has been made to solve the above-mentioned drawings of the prior art, and to provide a therapeutic drug for an endotoxin blood symptom and multi-organ failure induced by it, which therapeutic drug will not produce drug-resistant bacteria unlike in the use of antibiotics, can exhibit excellent therapeutic effects against various Gram-negatic bacteria, and enables the continuous treatment with high safety for human bodies.
In order to solve the above problems, the present inventors have noted diseases induced by the physiological activities of the endotoxins, and looked for medicines for reducing the appearance of such physiological activities. Then, the inventors looked for medicines capable of reducing the shock death with the endotoxins. As a result, they discovered that the shock death which might be caused by the administration of the endotoxin can be reduced with sialic acid or its polymer.
The present invention has been accomplished as mentioned above. A first invention is directed as its gist to a therapeutic drug composed of sialic acid or its salt as an effective ingredient and adapted for an endotoxin blood symptom and multi-organ failure induced by the endotoxin blood symptom. A second invention is directed as its as its gist to a therapeutic drug composed of a polymer of sialic acid or a salt of the polymer as an effective ingredient and adapted for an endotoxin blood symptom and multi-organ failure induced by the endotoxin blood symptom. As the polymer of sialic acid, polymers composed of two to thirteen sialic acid units may be used. The upper limit is posed upon the polymer composed of thirteen sialic acid units, because polymers composed of up to thirteen sialic acid units can be favorably produced. With respect to the polymers composed of two to thirteen sialic acid units and salts of such polymers, physiological effects similar to those of sialic acid and its salts can be expected. As the salts of sialic acid and its polymers, various pharmacologically acceptable salts may be used. As salts of a monomer of sialic acid, a sodium salt, a potassium salt, a calcium salt and a magnesium salt are ordinarily used. As salts of the polymers of sialic acid units, sodium salts are ordinarily used. xe2x80x9cSialic acidxe2x80x9d used in the present specification means xe2x80x9cN-acetylneuraminic acidxe2x80x9d.
As pharmaceutical preparations of the present invention, oral administration preparations such as tablets, capsules and powders, percutaneous absorption preparations such as suppository and vaginal suppository, and injections such as subcutaneous injection, intraperitoneal injections, and intravenous injections may be recited. Oral administration preparations are most preferable for preventing the diseases, and injections are most preferable for emergency use.
Oral administration preparations, percutaneous absorption preparations and injections can be formulated in ordinarily medicine-preparing methods. Formulating examples of an oral administration preparation and an injection are as follows.
1) Example of an Injection Preparation
After 50 g of sialic acid or its polymer is dissolved into 1000 ml of distilled water (free from pyrogen), the resulting solution is adjusted to pH 7.0 by using a solution of caustic soda, and filtered and sterilized by ordinary methods. Then, the sterilized filtrate is sealingly and aseptically charged into a 20 ml ample in the form of an injection.
A capsulated preparation is produced by charging 280 mg of sialic acid or its polymer having passed a 60 mesh sieve into a No. 3 gelatin capsule.
A higher effect can be obtained in the administration of the pharmaceutical preparation of the present invention in the case that the preparation begins to be administrated to a infected person, particularly when he or she is turned to be infected with Gram-negative bacteria as compared with a case where the administration is begun after confirmation of any endotoxin blood symptom. Although an administrated dosage varies depending upon age, sex, disease degree, etc. of the patient, the dosage cannot be generally defined. However, when calculated as a sodium salt of sialic acid or its polymer contained in an injection, 1 to 2000 mg/Kg, preferably 10 to 500 mg/Kg, may be administrated to one adult per day. The number of administrations is appropriately one to six times per day. Venous instillation is an effective administration.
Since sialic acid is a substance which is much contained in terminals of saccharides present in surface layers of cells constituting the human body, and terminals of succharides present in the blood and the body fluid, the pharmaceutical preparations are medicines which give extremely small adverse effects upon the human body.
Sialic acid and its polymers used in the present invention may be either one of synthesized chemical products, enzymatically catalyzed synthesis products obtained by using sialic acid aldolase, cytosine monophosphate-N-acetylneuraminic acid (CMP-NANA) synthesis enzyme or CMP-NANA transferase and a hydrolyzed product of colominic acid obtained by decomposing colominic acid with an acid. But, they are not restrictive.
The endotoxin blood symptom and the multi-organ failure induced by it can be effectively medically treated with the therapeutic drug according to the present invention.